Targeting alveolar-specific succinate dehydrogenase A attenuates pulmonary inflammation during acute lung injury.
Christine U VohwinkelEthan J CoitNana BurnsHanan ElajailiDaniel Hernandez-SaavedraXiaoyi YuanTobias EckleEva NozikRubin M TuderHolger K EltzschigPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2021)
Acute lung injury (ALI) is an inflammatory lung disease, which manifests itself in patients as acute respiratory distress syndrome (ARDS). Previous studies have implicated alveolar-epithelial succinate in ALI protection. Therefore, we hypothesized that targeting alveolar succinate dehydrogenase SDH A would result in elevated succinate levels and concomitant lung protection. Wild-type (WT) mice or transgenic mice with targeted alveolar-epithelial Sdha or hypoxia-inducible transcription factor Hif1a deletion were exposed to ALI induced by mechanical ventilation. Succinate metabolism was assessed in alveolar-epithelial via mass spectrometry as well as redox measurements and evaluation of lung injury. In WT mice, ALI induced by mechanical ventilation decreased SDHA activity and increased succinate in alveolar-epithelial. In vitro, cell-permeable succinate decreased epithelial inflammation during stretch injury. Mice with inducible alveolar-epithelial Sdha deletion (Sdhaloxp/loxp SPC-CreER mice) revealed reduced lung inflammation, improved alveolar barrier function, and attenuated histologic injury. Consistent with a functional role of succinate to stabilize HIF, Sdhaloxp/loxp SPC-CreER experienced enhanced Hif1a levels during hypoxia or ALI. Conversely, Hif1aloxp/loxp SPC-CreER showed increased inflammation with ALI induced by mechanical ventilation. Finally, wild-type mice treated with intra-tracheal dimethlysuccinate were protected during ALI. These data suggest that targeting alveolar-epithelial SDHA dampens ALI via succinate-mediated stabilization of HIF1A. Translational extensions of our studies implicate succinate treatment in attenuating alveolar inflammation in patients suffering from ARDS.
Keyphrases
- mechanical ventilation
- acute respiratory distress syndrome
- wild type
- intensive care unit
- extracorporeal membrane oxygenation
- oxidative stress
- endothelial cells
- respiratory failure
- mass spectrometry
- high fat diet induced
- transcription factor
- end stage renal disease
- newly diagnosed
- ejection fraction
- cancer therapy
- prognostic factors
- single cell
- stem cells
- metabolic syndrome
- insulin resistance
- cell therapy
- replacement therapy
- adipose tissue
- capillary electrophoresis
- liquid chromatography